Search

[Display omitted] The high activity barriers of Li 2 S nucleation and deposition limit the redox reaction kinetics of lithium polysulfides (LiPSs), meanwhile, the significant shuttle effect of LiPSs hampers the advancement of Li-S batteries (LSBs). In this work, a NiSe 2 /CoSe 2 -rGO (NiSe 2 /CoSe 2 -G) sulfur host with bifunctional catalytic activity was prepared through a hard template method. Electrochemical experiment results confirm that the combination of NiSe 2 and CoSe 2 not only facilitates the bidirectional catalytic function during charge and discharge processes, but also increases the active sites toward LiPSs adsorption. Simultaneously, the highly conductive rGO network enhances the electronic conductivity of NiSe 2 /CoSe 2 -G/S and provides convenience for loading NiSe 2 /CoSe 2 catalysts. Benefitting from the exceptional catalytic-adsorption capability of NiSe 2 /CoSe 2 and the presence of rGO, the NiSe 2 /CoSe 2 -G/S electrode exhibits excellent electrochemical properties. At 1C, it demonstrates a low capacity attenuation of 0.087 % per cycle during 500 cycles. The electrode can maintain a discharge capacity of 927 mAh/g at a sulfur loading of 3.3 mg cm−2. The bidirectional catalytic activity of NiSe 2 /CoSe 2 -G offers a prospective approach to expedite the redox reactions of active S, meanwhile, this work also offers an ideal approach for designing efficient S hosts for LSBs. [ABSTRACT FROM AUTHOR]

[Display omitted] • Mesoporous carbon (MC) supported MgO catalysts were prepared by impregnation method. • MgO are highly dispersed on the surface of MC through metal-support interaction. • MgO/MC can efficiently catalyze transesterification of diethyl carbonates with alcohols. • Various unsymmetrical organic carbonates can be obtained at ambient temperature. • MgO/MC exhibit high stability and recyclability for transesterification reaction. Transesterification of dialkyl carbonate with various alcohols is a very attractive route for synthesizing unsymmetrical organic carbonates. Intensive efforts have been focused on developing highly active and stable heterogeneous catalysts that can efficiently catalyze the transesterification reaction at mild conditions. In this work, the synthesis of unsymmetrical organic carbonates was conducted over a series of mesoporous carbon-supported MgO (MgO/MC) catalysts. The composition-optimized MgO/MC catalyst exhibited remarkably high activity, selectivity and stability for the transesterification of diethyl carbonates with various alcohols at the commonly used reaction temperature of 125 °C, and could even work well at ambient temperature. The uniformly dispersed MgO species should be the main active sites for the transesterification reaction, while the neighboring oxygen- and nitrogen-containing groups existed on the surface of MC support may also play positive role in synergistically activating the reagents, thus leading to efficient production of the corresponding unsymmetrical organic carbonates at very mild conditions. [ABSTRACT FROM AUTHOR]

Physics-informed neural networks (PINNs) have emerged as a significant endeavour in recent years to utilize artificial intelligence technology for solving various partial differential equations (PDEs). Nevertheless, the vanilla PINN model structure encounters challenges in accurately approximating solutions at hard-to-fit regions with, for instance, "stiffness" points characterized by fast-paced alterations in timescale. To this end, we introduce a novel model architecture based on PINN, named loss-attentional physics-informed neural networks (LA-PINN), which equips each loss component with an independent loss-attentional network (LAN). Feeding the squared errors (SE) on every training point into LAN as the input, the attentional function is then built by each LAN and provides different weights to diverse point SE s. A point error-based weighting approach that utilizes the adversarial training between multiple networks in the LA-PINN model is proposed to dynamically update weights of SE during every training epoch. Additionally, the weighting mechanism of LA-PINN is analysed and also be validated by performing several numerical experiments. The experimental results indicate that the proposed method displays superior predictive performance compared to the vanilla PINN and holds a swift convergence characteristic. Moreover, it can advance the convergence of those hard-to-fit points by progressively increasing the growth rates of both the weight and the update gradient for point error. • A novel PINN architecture that pays attention to all point errors and dynamically weights them during training. • A framework that leverages multi-network collaboration through adversarial training to facilitate the convergence of the model. • The proposed method has fast convergence characteristics with high accuracy in solving several benchmark PDEs. • Enhance the convergence in the "stiffness" region, a consistent challenge when solving PDEs using PINNs. [ABSTRACT FROM AUTHOR]

Patients with chronic pain often experience memory impairment, but the underlying mechanisms remain elusive. The myelin sheath is crucial for rapid and accurate action potential conduction, playing a pivotal role in the development of cognitive abilities in the central nervous system. The study reveals that myelin degradation occurs in the hippocampus of chronic constriction injury (CCI) mice, which display both chronic pain and memory impairment. Using fiber photometry, we observed diminished task-related neuronal activity in the hippocampus of CCI mice. Interestingly, the repeated administration with clemastine, which promotes myelination, counteracts the CCI-induced myelin loss and reduced neuronal activity. Notably, clemastine specifically ameliorates the impaired memory without affecting chronic pain in CCI mice. Overall, our findings highlight the significant role of myelin abnormalities in CCI-induced memory impairment, suggesting a potential therapeutic approach for treating memory impairments associated with neuropathic pain. • Patients with chronic pain show memory impairment. • Mice with chronic constriction injury (CCI) display both chronic pain and memory impairment. • Diminished task-related neuronal activity and myelin loss occurs in the hippocampus of CCI mice. • Cemastine improved the CCI-induced myelin loss and reduced neuronal activity in CCI mice. [ABSTRACT FROM AUTHOR]

Previous studies have shown that some inflammatory cytokines promote the expression of corticotropin-releasing hormone (CRH) in trophoblasts during pregnancy and that placental CRH could induce the production of adrenocorticotropic hormone (ACTH) in humans. However, whether the same is true in rodent placenta remains unclear. In this study, we examined the effect of pro-inflammatory cytokine LIF on the induction of CRH in mouse trophoblast stem cells (mTSCs). During differentiation, the CRH levels in mTSCs gradually increased. On days 3 and 5 after LIF supplementation, Crh expression in the differentiated mTSCs was significantly increased with LIF treatment than those without LIF treatment. Moreover, the CRH concentration in the culture media increased. Thereafter, we examined the contribution of the downstream pathways of LIF to CRH induction in differentiated mTSCs. The LIF-induced upregulation of CRH was attenuated by inhibition of PI3K/AKT and MAPK phosphorylation but not by inhibition of JAK/STAT3. Therefore, in mTSCs, LIF increased Crh expression through activation of the PI3K/AKT and MAPK pathways but not by the JAK/STAT3 pathway. The present study suggests that mTSC is an ideal in vitro model for studying regulation and function of placental CRH. • Corticotropin-releasing hormone was expressed in mouse trophoblast stem cells and increased during their differentiation. • Leukemia inhibitory factor induced corticotropin-releasing hormone in mouse trophoblast stem cells. • PI3K/AKT and MAPK but not JAK/STAT3 pathways mediated LIF-induced CRH expression in mouse trophoblast stem cells. • Mouse trophoblast stem cell is an ideal in vitro model for studying regulation and function of placental CRH. [ABSTRACT FROM AUTHOR]

Hyperglycemia-induced endothelial dysfunction is generally believed to be the basis of diabetic vascular complications. Dopamine receptors is known to play an important protective role in diabetes. However, the protective effect of dopamine receptors against hyperglycemia-induced endothelial damage in diabetic rats is still unknown. In the present study, we established a cell model of hyperglycemia-induced endothelial dysfunction by treating human umbilical vein endothelial cells (HUVEC) with high glucose. MTT and lactate dehydrogenase assays results showed that high glucose treatment significantly reduced the cell viability and down-regulated dopamine D 4 receptor. Pre-treatment with PD168077, a specific D 4 receptor agonist, greatly improved endothelial cell viability and decreased apoptosis. Furthermore, pharmacological inhibition of phosphoinositide 3-kinase (PI3K) and endothelial nitric oxide synthase (eNOS) eliminated the protective effect of D 4 receptor against endothelial injury. More importantly, the expression level of D 4 receptor was also dramatically down-regulated in the arterial endothelium of rats with streptozotocin-(STZ)-induced diabetes, and the STZ-induced impairment of acetylcholine-induced vasodilation was reversed by activation of D 4 receptor. In conclusion, our results indicated that dopamine D 4 receptor protected against hyperglycemia-induced endothelial dysfunction via the PI3K/eNOS pathway, which may provide a novel strategy in the treatment of diabetes. • Dopamine D4 receptor is down-regulation in hyperglycemia-induced endothelial dysfunction. • D4 receptor agonist greatly improved endothelial cell viability and decreased apoptosis. • Protective effect of D4 receptor against endothelial injury is via PI3K/Akt/eNOS/NO pathway. [ABSTRACT FROM AUTHOR]

The group of basis-conjugating automorphisms of the free group of rank n , also known as the McCool group or the welded braid group P Σ n , contains a much-studied subgroup, called the upper McCool group P Σ n +. Starting from the cohomology ring of P Σ n + , we find, by means of a Gröbner basis computation, a simple presentation for the infinitesimal Alexander invariant of this group, from which we determine the resonance varieties and the Chen ranks of the upper McCool groups. These computations reveal that, unlike for the pure braid group P n and the full McCool group P Σ n , the Chen ranks conjecture does not hold for P Σ n + , for any n ≥ 4. Consequently, P Σ n + is not isomorphic to P n in that range, thus answering a question of Cohen, Pakianathan, Vershinin, and Wu. We also determine the scheme structure of the resonance varieties R 1 (P Σ n +) , and show that these schemes are not reduced for n ≥ 4. [ABSTRACT FROM AUTHOR]

Amphibian skin secretions contain biologically-active compounds, such as anti-microbial peptides and trypsin inhibitors, which are used by biomedical researchers as a source of potential novel drug leads or pharmacological agents. Here, we report the application of a recently developed technique within our laboratory to “shotgun” clone the cDNAs encoding two novel but structurally-related peptides from the lyophilised skin secretions of one species of European frog, Rana esculenta and one species of Chinese frog, Odorrana schmackeri . Bioanalysis of the peptides established the structure of a 17-mer with an N-terminal Ala (A) residue and a C-terminal Cys (C) residue with a single disulphide bridge between Cys 12 and 17, which is a canonical Kunitz-type protease inhibitor motif (-CKAAFC-). Due to the presence of this structural attribute, these peptides were named kunitzin-RE (AAKIILNPKFRCKAAFC) and kunitzin-OS (AVNIPFKVHLRCKAAFC). Synthetic replicates of these two novel peptides were found to display a potent inhibitory activity against Escherichia coli but were ineffective at inhibiting the growth of Staphylococcus aureus and Candida albicans at concentrations up to 160 μM, and both showed little haemolytic activity at concentrations up to 120 μM. Subsequently, kunitzin-RE and kunitzin-OS were found to be a potent inhibitor of trypsin with a Ki of 5.56 μM and 7.56 μM that represent prototypes of a novel class of highly-attenuated amphibian skin protease inhibitor. Substitution of Lys-13, the predicted residue occupying the P1 position within the inhibitory loop, with Phe (F) resulted in decrease in trypsin inhibitor effectiveness and antimicrobial activity against Esherichia coli , but exhibits a potential inhibition activity against chymotrypsin. [ABSTRACT FROM AUTHOR]

The amphibian temporins, amongst the smallest antimicrobial peptides (AMPs), are α-helical, amphipathic, hydrophobic and cationic and are active mainly against Gram-positive bacteria but inactive or weakly active against Gram-negative bacteria. Here, we report two novel members of the temporin family, named temporin-1Ee (FLPVIAGVLSKLF amide ) and temporin-1Re (FLPGLLAGLL amide ), whose biosynthetic precursor structures were deduced from clones obtained from skin secretion-derived cDNA libraries of the European edible frog, Pelophylax kl. esculentus , by ‘shotgun’ cloning. Deduction of the molecular masses of each mature processed peptide from respective cloned cDNAs was used to locate respective molecules in reverse-phase HPLC fractions of secretion. Temporin-1Ee (MIC = 10 μM) and temporin-1Re (MIC = 60 μM) were both found to be active against Gram-positive Staphylococcus aureus , but retaining a weak haemolytic activity. To our knowledge, Single-site substitutions can dramatically change the spectrum of activity of a given temporin. Compared with temporine-1Ec, just one chemically-conservative substitution (Val8 instead of Leu8), temporin-1Ee bearing a net charge of +2 displays broad-spectrum activity with particularly high potency on the clinically relevant Gram-negative strains, Escherichia coli (MIC = 40 μM). These factors bode well for translating temporins to be potential drug candidates for the design of new and valuable anti-infective agents. [ABSTRACT FROM AUTHOR]

Accumulating evidence has indicated that natural killer cells (NK cells) play an important role in immune responses generated in the liver. However, the underlying molecular basis for local immune regulation is poorly understood. Mice were intraperitoneally injected with polyinosinic-polycytidylic acid (PolyI:C) at a dose of 20 mg/kg body wt. The percentage and absolute number of NK cells in the liver were analysed with flow cytometry. LSECtin knockout mice and LSECtin cDNA plasmids were used for analyze the role of LSECtin in hepatic NK cell regulation in vivo. Here, we show that the C-type lectin LSECtin, a member of the DC-SIGN family, is a novel liver regulator for NK cells. LSECtin could bind to NK cells in a carbohydrate-dependent manner and could regulate the number of hepatic NK cells. In the NK cell-mediated acute liver injury model induced with PolyI:C, the exogenous expression of LSECtin accelerated NK cell-induced liver injury, whereas the absence of LSECtin ameliorated this condition. Our results reveal that LSECtin is a novel, liver-specific NK cell regulator that may be a target for the treatment of inflammatory diseases in the liver. [ABSTRACT FROM AUTHOR]

Ferrihydrite (Fh), a precursor of more crystalline Fe (hydr)oxides, exhibits decent catalytic behavior; however, the instability of its amorphous structure limits its engineering applications. Siliceous ferrihydrite (FhSi) was readily synthesized in this study by co-precipitation. The formation of Fe–O–Si linkages did not alter the amorphous state of pure Fh, but increased the surface area (S BET), reduced the point of zero charge (pH ZPC), and prevented the leaching of more iron. X-ray diffraction, Mössbauer and pyridine-Fourier transform infrared (FTIR) spectroscopies, and potentiometric titration revealed the presence of silicon-occupied portions of growth sites on the Fh surface, which increased the coordination symmetry around the Fe atom and inhibited the transition of Fh to more stable crystalline Fe (hydr)oxides during repeated use. Meanwhile, the density of surface hydroxyl groups (Ds) and the total acid content of the catalytic system after five cycles of catalytic ozonation were 56.75 % and 63.58 % higher than those of freshly prepared system, thereby benefiting the catalysis of ozone for generating ·OH. In addition, the lower pH ZPC of the FhSi/O 3 system compared to that of the Fh/O 3 system promoted the generation of neutral surface-hydroxyl species on the surface of FhSi, which enabled a decent catalytic performance in alkaline solutions, regardless of the catalytic cycle. Moreover, the removal of humic acids (HA) followed a hydroxy radical reaction, which involved self-decomposition (14.15 %), catalytic ozonation (21.58 %), and peroxone and Fenton-like reactions (64.27 %). • Siliceous ferrihydrite (FhSi) samples were synthesized by co-precipitation. • FhSi was used as an ozonation catalyst to study the degradation of humic acids. • Surface properties/stability of FhSi in multiple catalytic ozonation were compared. • Catalytic performance of FhSi was examined under different pH conditions. • Contributions of active species and reactions in catalytic ozonation were probed. [ABSTRACT FROM AUTHOR]

Abstract: The proprotein convertases subtilisin kexin 9 (PCSK9) binds to the epidermal growth factor domain A (EGF-A) of low-density lipoprotein receptor (LDLR) and leads to its destruction. However, the intracellular processes leading to LDLR degradation have not been fully delineated. In this report, we show that PCSK9 treatment can lead to ubiquitination of LDLR, which was enhanced in the presence of proteasome inhibitor MG132. Furthermore, LDLR protein carrying mutations in the C-terminal ubiquitination sites was resistant to PCSK9-mediated degradation. Our data suggest that the ubiquitination system is involved in PCSK9-induced LDLR degradation. [Copyright &y& Elsevier]

Abstract: Large species differences in the expression of carboxylesterases (CE) have been described, but the interrelationships of CEs across species are not well characterized. In the current analyses, sequences with genomic structures similar to human CEs were found in piscine, avian, and mammalian genomes. Analyses of these genes suggest that four CE groups existed prior to mammalian divergence, with another form occurring after eutherian–marsupial divergence, yielding five distinct mammalian CE groups. The CE1 and CE2 groupings appear to have undergone extensive gene duplication in species with herbivorous and omnivorous diets underscoring the potential importance of these two groups in xenobiotic metabolism. However, CE3, CE4, and CE5 have remained at one gene per species in almost all observed cases. In avian and piscine genomes, only two CE groupings each were observed in the currently available sequence data. Finally, this study presents considerations for a broader phylogenetic-based nomenclature that could encompass other serine hydrolases in addition to the CEs. [Copyright &y& Elsevier]

Abstract: A rapid method to screen and identify unknown bound proteins to specific nucleic acid probes anchored on ProteinChip array surfaces from crude biological samples has been developed in this paper. It was demonstrated with screening specific binding proteins from LPS-stimulated mouse 70Z/3 pre-B cell nuclear extracts by direct coupling of thioaptamer XBY-S2 to the pre-activated ProteinChip array surfaces. With pre-fractionation of crude nuclear extracts by ion exchange method, specific “on-chip” captured proteins have been obtained that were pure enough to do “on-chip” digestion and the subsequent identification of the “on-chip” bound proteins by microsequencing of the trypsin digested peptide fragments through tandem MS. Five mouse heterogeneous nuclear ribonucleoproteins (hnRNPs) A1, A2/B1, A3, A/B, and D0 were identified. To verify those bound hnRNPs, a novel thioaptamer/antibody sandwich assay provides highly sensitive and selective identification of proteins on ProteinChip arrays. [Copyright &y& Elsevier]

Peripheral electrical stimulation (PES) has been utilized to manage chronic pain associated with nerve injury. However, the data on clinical effectiveness are conflicting and the neurophysiological mechanism is not well known. This study was designed to assess whether PES relieved neuropathic pain and its possible mechanisms. The neuropathic pain model was made with lumbar 5th (L5) and 6th (L6) spinal nerve ligations in rats. Nociceptive responses of the rats were assessed by the cold plate test (the number and duration of paw lifts that occurred in 5 min on a 5 ± 1°C cold plate). PES with a frequency of 2 Hz and at increasing strengths was given for 30 min via stainless-steel needles inserted into standard acupoints on the leg and back, respectively. Immunochemistry was used to examine the immunoreactivity of the NMDA receptor 1 (NR1) subunit in the spinal cord dorsal horn. The results are as follows: (1) PES relieved neuropathic pain and the effect was blocked by 1.0 mg/kg naloxone. (2) The effect of one session of PES lasted up to 12 h. (3) Repetitive PES showed a cumulative effect and no tolerance was observed. (4) There was a significant increase of NR1 immunoreactivity in the superficial laminae of the spinal cord of neuropathic pain rats as compared with naive rats. This increase could be reversed by repetitive 2 Hz PES. These results suggest that PES can relieve neuropathic pain, and that μ-opioid receptors and NMDA receptors are involved in the effect of PES. [Copyright &y& Elsevier]

This study examined whether retarded angiogenesis in a hypertension animal model was associated with impaired VEGF signaling. Furthermore, we sought to determine whether this impairment could be overcome by VEGF addition. Using a rat sponge implantation model, we confirmed impaired angiogenesis in spontaneous hypertensive rats (SHRs). Fourteen days after sponge implantation, the level of angiogenesis in SHRs was approximately half of those in age-matched normotensive Wistar–Kyoto or Sprague–Dawley rats. Significantly, expression of kinase-insert domain-containing receptor (KDR) and membrane type 1 matrix metalloproteinase (MT1-MMP) was reduced in SHRs compared to controls. Immunohistological analysis indicated endothelial proliferation was decreased in SHRs. Gene transfer of human VEGF121 increased KDR and MT1-MMP expression in SHRs. VEGF121 also up-regulated endothelial proliferation and angiogenesis. Our results indicate down-regulated KDR and MT1-MMP expression is associated with an impaired angiogenesis in SHRs. VEGF gene transfer is effective in ameliorating the impaired angiogenesis in SHRs. [Copyright &y& Elsevier]

PDK1 (3-Phosphoinositide dependent protein kinase-1) is a member in the PI3K (phosphatidylinositol 3 kinase) pathway and is implicated in neurodevelopmental disease with microcephaly. Although the role of PDK1 in neurogenesis has been broadly studied, it remains unknown how PDK1 may regulate oligogenesis in the central nervous system (CNS). To address this question, we generated oligodendrocyte (OL) lineage cells specific PDK1 conditional knockout (cKO) mice. We find that PDK1 cKOs display abnormal white matter (WM), massive loss of mature OLs and severe defect in myelination in the CNS. In contrast, these mutants exhibit normal neuronal development and unchanged apoptosis in the CNS. We demonstrate that deletion of PDK1 severely impairs OL differentiation. We show that genetic or pharmacological inhibition of PDK1 causes deficit in the mammalian target of rapamycin (mTor) signaling and down-regulation of Sox10. Together, these results highlight a critical role of PDK1 in OL differentiation during postnatal CNS development. • Deletion of PDK1 in oligodendrocyte lineages causes myelination defect and loss of mature OLs in the central nervous system. • Deletion of PDK1 in oligodendrocyte lineages leads to severe impairment in oligodendrocyte differentiation. • Deletion of PDK1 results in down-regulation of Sox10 in the white matter. Pharmacological inhibition of PDK1 significantly reduces Sox10 levels in an oligodendroglial cell line. • PDK1 controls oligodendrocyte differentiation through regulation on the expression of Sox10 and oligodendrocyte-specific genes. [ABSTRACT FROM AUTHOR]

In the process of production of freshwater pearl, implanted mantle pieces undergo a series of complex physiological and biochemical processes to form pearl sac, which produce pearl. This is a very important site of occurrence due to immune-induced biomineralization, while its molecular regulatory mechanism is still unclear. Here, we use proteomics to identify differentially expressed proteins (DEPs) of the mantle and pearl sac and examine the biomineralization and immune response of the pearl sac formation process in Hyriopsis cumingii. Using iTRAQ technology and bioinformatics analysis, we obtained DEP profiles between the mantle and pearl sac. A total of 1871 proteins were identified. Of these, 74 DEPs were found between the pearl sac and outer mantle, 112 DEPs between the pearl sac and inner mantle, and 124 DEPs between the outer and inner mantles. Bioinformatics analysis revealed that the screened biomineralization-related DEPs were mainly enriched in signaling pathways associated with calcium signaling, regulation of the actin cytoskeleton and protein processing in the endoplasmic reticulum, while the immune-related DEPs were mainly enriched in the Notch, Hippo, nuclear factor kappa-B (NF-κB), and transforming growth factor-β (TGF-β) signaling pathways. In addition, the expression of six biomineralization-related and four immune-related proteins were verified at the transcriptional level using quantitative real-time PCR. Our findings contribute to furthering the understanding of the mechanisms of pearl formation and immune response, and have long-term implications for future studies on the production of high-quality freshwater pearls and development of the freshwater pearl industry. • We used comparative proteomics to analyze immune- and biomineralization-associated DEPs and analyzed the possible joint role of both in the process of pearl sac formation. • We subdivided the mantle into outer mantle and inner mantle and compared them with each other with the pearl sac. • Our data will contribute to the understanding of the molecular mechanisms involved in pearl formation and will have implications for future research on the production of freshwater pearls. [ABSTRACT FROM AUTHOR]

[Display omitted] In the semiconductor/molecule/metal system, enhancing the efficiency of the charge-transfer (CT) plays a pivotal role in improving the sensitivity of semiconductor-based surface-enhanced Raman scattering (SERS). In this work, use of SERS for detection of an enhanced CT in a chemically-etched Al-doped ZnO (AZO), 4-mercaptopyridine (MPy) molecule, and Ag nanoparticles (NPs) (AZO/MPy/Ag) sandwich structure is reported. A series of CT routes are proposed in the energy level diagram of AZO/MPy/Ag assemblies under the excitation line at 633 nm. Very interestingly, for the first of its kind, a significant CT route from the conduction band (CB) of AZO to the lowest unoccupied molecular orbital (LUMO) of MPy molecule is detected. This route can remarkably improve the degree of CT in the AZO/MPy/Ag system by about 48% compared with that of the ZnO/MPy/Ag system. Furthermore, the uniquely enhanced CT route is also further confirmed by alternative probe molecules like p-aminothiophenol (PATP) and 4-mercaptobenzoic acid (MBA). The discovery of this extra CT route will inevitably play an irreplaceable role in SERS enhancement through its participating in the CT enhancement mechanism. [ABSTRACT FROM AUTHOR]

• The first study to identify genes associated with voxel-mirrored homotopic connectivity (VMHC) alterations in patients with schizophrenia using the transcription-neuroimaging association analysis approach. • This study determined the biological functions of the identified genes, as well as the cell types, brain regions and developmental stages in which they were enriched. • We also found cognitive processes related to VMHC alterations in schizophrenia. • The findings offer novel insights into the genetic mechanisms of schizophrenia-related VMHC alterations. It has been revealed that abnormal voxel-mirrored homotopic connectivity (VMHC) is present in patients with schizophrenia, yet there are inconsistencies in the relevant findings. Moreover, little is known about their association with brain gene expression profiles. In this study, transcription-neuroimaging association analyses using gene expression data from Allen Human Brain Atlas and case-control VMHC differences from both the discovery (meta-analysis, including 9 studies with a total of 386 patients and 357 controls) and replication (separate group-level comparisons within two datasets, including a total of 258 patients and 287 controls) phases were performed to identify genes associated with VMHC alterations. Enrichment analyses were conducted to characterize the biological functions and specific expression of identified genes, and Neurosynth decoding analysis was performed to examine the correlation between cognitive-related processes and VMHC alterations in schizophrenia. In the discovery and replication phases, patients with schizophrenia exhibited consistent VMHC changes compared to controls, which were correlated with a series of cognitive-related processes; meta-regression analysis revealed that illness duration was negatively correlated with VMHC abnormalities in the cerebellum and postcentral/precentral gyrus. The abnormal VMHC patterns were stably correlated with 1287 genes enriched for fundamental biological processes like regulation of cell communication, nervous system development, and cell communication. In addition, these genes were overexpressed in astrocytes and immune cells, enriched in extensive cortical regions and wide developmental time windows. The present findings may contribute to a more comprehensive understanding of the molecular mechanisms underlying VMHC alterations in patients with schizophrenia. [ABSTRACT FROM AUTHOR]

• Modal controllability and synchronizability increase in the internet gaming addicts. • Addiction mediates the relationship between brain controllability and anxiety state. • Regional morphometry is associated with the brain controllability. • Specific regional controllability could deeply affect brain states. Internet gaming addiction (IGD) is a common disease in teenagers which usually reflects the abnormalities in brain function or structure. Several computational models have been applied to investigate the characteristic of IGD brain networks, for instance, the conception of brain controllability. The primary objective of this study was to explore the relationship between brain controllability and IGD related clinical behaviour. A sample of 101 subjects, including 49 IGD patients and 52 normal controls, were recruited to undergo MR T1 and DTI scanning. Specifically, the MR images were used to generate the white matter connectivity matrix and the morphometry similarity network. The morphometry similarity network was then divided into several communities using modular decomposition. After, average controllability, modal controllability and synchronizability were calculated through measuring the adjacency matrix. The results indicated that the IGD group had greater synchronizability and modal controllability compared to that of the control group, and different morphological-based brain communities had different controllability properties. Furthermore, the addiction demonstrated the mediating effects between nodal or modular brain controllability as well as anxiety. In conclusion, brain controllability could be a potential biomarker of IGD. [ABSTRACT FROM AUTHOR]

Gait disturbance is a manifestation of cerebral small vessel disease (CSVD). The posterolateral thalamus (PL), whose blood is mainly supplied by the P2 segment of posterior cerebral artery (P2-PCA), plays pivotal roles in gait regulation. We investigated the influence of the distance between P2-PCA and PL on gait with varying CSVD burden. 71 participants were divided into low and high CSVD burden groups. The distance from P2-PCA to PL was measured using 7 T TOF-MRA and categorized into an immediate or distant PCA-to-thalamus pattern. Functional connectivity (FC) and voxel-based morphometry were assessed to evaluate functional and structural alterations. In the low CSVD burden group, immediate PCA-to-thalamus supply strongly correlates with longer step length and higher wave phase time percent, and exhibited enhanced FCs in left supplementary motor area, right precentral cortex (PreCG.R). While in the high CSVD burden group, no association between PCA-to-thalamus pattern and gait was found, and we observed reduced FC in PreCG.R with immediate PCA-to-thalamus pattern. Higher CSVD burden was associated with decreased gray matter density in bilateral thalamus. However, no significant structural thalamic change was observed between the two types of PCA-to-thalamus patterns in all patients. Our study demonstrated patients with immediate PCA-to-thalamus supply exhibited better gait performance in low CSVD burden populations, which also correlated with enhanced FCs in motor-related cortex, indicating the beneficial effects of the immediate PCA-to-thalamus supply pattern. In the higher burden CSVD populations, the effects of PCA-to-thalamus pattern on gait are void, attributable to the CSVD-related thalamic destruction and impairment of thalamus-related FC. • The vascular structure of the brain may potentially influence gait performance of individuals with CSVD • A shorter distance between the P2-PCA and the posterolateral thalamus prompts better gait performance in patients with a low CSVD burden • This correlation between PCA-to-thalamus vascular supply pattern and gait is not observed in those with a high CSVD burden • Neuroimaging can be instrumental in identifying individuals at a high risk of gait disturbances with low CSVD burden [ABSTRACT FROM AUTHOR]

• Photoactive and transition metal catalytic property of Cu n X n. • Redox ferrocene as electron shuttle to stabilize intermediates. • Mild reaction conditions and good functional group tolerance. This study investigated a series of ferrocenyltelluroether based cuprous halide clusters as effective single-molecule metallaphotocatalysts (SMP) in white light-driven C H arylation at room temperature and air. A systematic mechanistic study reveals that Cu(I) cluster can be irradiated by visible light to promote proton-coupled electron transfer (PCET), during which the electron from Cu(I)* leaves together with the proton from benzothiazole C H, leading to the formation of benzothiazolate-coordinated Cu(II) intermediate and aryl radical. Subsequently, the electron transfer (ET) from the ferrocene unit to the Cu(II) center releases the reactive benzothiazolate to form the target product with aryl radical. The advantages of these copper(I) halide clusters as SMP include high photocatalytic efficiency, structure adjustability, mild reaction conditions and good functional group tolerance. [ABSTRACT FROM AUTHOR]

Quantitative susceptibility mapping (QSM) has demonstrated great potential in quantifying tissue susceptibility in various brain diseases. However, the intrinsic ill-posed inverse problem relating the tissue phase to the underlying susceptibility distribution affects the accuracy for quantifying tissue susceptibility. Recently, deep learning has shown promising results to improve accuracy by reducing the streaking artifacts. However, there exists a mismatch between the observed phase and the theoretical forward phase estimated by the susceptibility label. In this study, we proposed a model-based deep learning architecture that followed the STI (susceptibility tensor imaging) physical model, referred to as MoDL-QSM. Specifically, MoDL-QSM accounts for the relationship between STI-derived phase contrast induced by the susceptibility tensor terms (χ 13 , χ 23 and χ 33) and the acquired single-orientation phase. The convolutional neural networks are embedded into the physical model to learn a regularization term containing prior information. χ 33 and phase induced by χ 13 and χ 23 terms were used as the labels for network training. Quantitative evaluation metrics were compared with recently developed deep learning QSM methods. The results showed that MoDL-QSM achieved superior performance, demonstrating its potential for future applications. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: Casitas B-lineage lymphoma b (Cblb) is a negative regulator of T-cell activation and dysfunction of Cblb in rats and mice results in autoimmunity. In particular, a nonsense mutation in Cblb has been identified in a rat model of autoimmune type 1 diabetes. To clarify the possible involvement of CBLB mutation in type 1 diabetes in humans, we performed mutation screening of CBLB and characterized functional properties of the mutations in Japanese subjects. Six missense mutations (A155V, F328L, N466D, K837R, T882A, and R968L) were identified in one diabetic subject each, excepting N466D. Of these mutations, F328L showed impaired suppression of T-cell activation and was a loss-of-function mutation. These data suggest that the F328L mutation is involved in the development of autoimmune diseases including type 1 diabetes, and also provide insight into the structure–function relationship of CBLB protein. [Copyright &y& Elsevier]

In visual perception, human only perceive discrete-scale quality levels over a wide range of coding bitrate. More clearly, the videos compressed with a series of quantization parameters (QPs) only have limited perceived quality levels. In this paper, perceptual quantization is transformed into the problem of how to determine the just perceived QP for each quality level, and a just noticeable coding distortion (JNCD) based perceptual quantization scheme is proposed. Specifically, multiple visual masking effects are analyzed and a linear regression (LR) based JNCD model is proposed to predict JNCD thresholds for all quality levels at first. According to the JNCD prediction model, the frame-level perceptual QPs for all quality levels are then derived on the premise of that coding distortions are infinitely close to the predicted JNCD thresholds. Based on the predicted frame-level perceptual QPs, the perceived QPs of all quality levels for each coding unit (CU) are finally determined according to a perceptual modulation function. Experimental results show that the proposed quality-wise perceptual quantization scheme is superior to the existing perceptual video coding algorithms significantly, i.e., the proposed perceptual quantization could save more bitrate with better quality. [ABSTRACT FROM AUTHOR]

Abstract Preparing transparent conducting oxide (TCO) layer is one of the critical procedures for the fabrication of CIGS solar cells. Especially conventional fabrication of TCO requires elevated temperature annealing process, which causes fatal effect for flexible CIGS solar cell grown on polyimide (PI) substrate. In this paper, we investigated the preparation method of aluminum-doped zinc oxide (AZO) and tin-doped indium oxide (ITO) bilayer thin films as the window layer by DC magnetron sputtering without annealing process. By varying the thickness of AZO and ITO, the bilayer thin films with high optical transmittance (>81.5% from 400 nm to 1200 nm) were achieved. The formation of ITO grains on AZO layer was analyzed by XRD and AFM. When the AZO thickness reached to 150 nm, an AZO-assisted ITO growth phenomenon was observed in our experiment, which was important for improving the electrical properties of bilayer structure. Compared to single layered (AZO or ITO) structure, the CIGS solar cells using bilayer structure enhanced photoelectric conversion efficiency (∼above 11%) and long-term stability. Highlights • We prepared AZO-ITO bilayer thin films by magnetron sputtering without annealing process. • We observed an AZO-assisted ITO growth phenomenon. • The long-term stability of CIGS solar cells was improved by capping AZO-ITO bilayer thin films. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is a common malignancy in male urinary system. Cell division cycle-associated protein 1 (CDCA1) is expressed highly in many cancer cells. Yet, whether CDCA1 play an important role in PCa progression is uncertain. pH low insertion peptide (pHLIP), a PH-induced transmembrane structure, can pass through the cell membrane into intracellular in an acidic environment. In this study, we try to confirm the expression status of CDCA1 in the PCa patients' tissues and PCa cell line. In addition, to make the CDCA1-siRNA efficiently targeting the PCa cells, pHLIP and CDCA1-siRNA were combined with disulfide bond to become effector molecules. By the characteristics of the pHLIP allosteric occurring in cancer tissue acidic microenvironment, CDCA1-siRNA may be transported specificity into prostatic cancer cells and released in the cytoplasm. The interference effect of the effector molecules on the CDCA1 was detected in vitro and in vivo. The results showed that CDCA1 was highly expressed in PCa cell line and human PCa clinical samples. Knock down CDCA1 significantly inhibit the growth and promote the apoptosis of prostatic cancer cells. In the intracellular translocation experiment, CDCA1-siRNA could be delivered into cytoplasma at pH 6.2, but not at pH 7.4. In the in vivo test, the tumor size was reduced obviously in the NOD/SCID mice treated with pHLIP-CDCA1-siRNA compared to the CDCA1-siRNA and the bioluminescent signal of Cy5-pHLIP-CDCA1-siRNA was focused detected in the tumor site. Our findings indicated that CDCA1 might be a very key molecule regulating survival and proliferation of PCa. pHLIP-CDCA1-siRNA might be a promising targeting therapy for PCa. [ABSTRACT FROM AUTHOR]

The development of gene-editing technology has been one of the biggest advances in biomedicine over the past two decades. Not only can it be used as a research tool to build a variety of disease models for the exploration of disease pathogenesis at the genetic level, it can also be used for prevention and treatment. This is done by intervening with the expression of target genes and carrying out precise molecular targeted therapy for diseases. The simple and flexible clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene-editing technology overcomes the limitations of zinc finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs). For this reason, it has rapidly become a preferred method for gene editing. As a new gene intervention method, CRISPR/Cas9 has been widely used in the clinical treatment of tumours and rare diseases; however, its application in the field of cardiovascular diseases is currently limited. This article reviews the application of the CRISPR/Cas9 editing technology in cardiovascular disease research and treatment, and discusses the limitations and prospects of this technology. [Display omitted] [ABSTRACT FROM AUTHOR]

• Cortical free water reflects properties of the cortical cellular morphology. • Relationship between the free water and CTH might reflect the cortical cellular status. • Combination of free water and macroscopic cortical features could potentially be used to reflect the hierarchal structures of healthy brain. We leveraged a novel index of diffusion MRI to investigate the relationships among cortical free water, macro-organizations and gene expression in healthy adults. Few research has been conducted to investigate the role of free water in the healthy adults due to it can easily be affected also by aging diseases. High quality data of 350 subjects from Human Connectome Project were used in our study. Cortical free water was estimated by using a bi-tensor model. The free water was high in the limbic, insular and somatosensory cortex, while being lower in motor and association cortex. The negative correlation between the free water and cortical thickness has been consistently identified in almost all the cortical regions. Negative correlation between the cortical free water and structural covariance (rho=-0.38, p spin =0.005) revealed the free water was sensitive to cortical heterogeneity. Using human gene expression dataset, we found the gene expression pattern of the relationship between the free water and cortical thickness spatially coupled with primary gradient of structural covariance network (rho=0.40, p spin =0.004). Our findings indicated the free water was sensitive to the cortical cellular status. The relationship between free water and macroscale organization also reflected hierarchal structures of cerebral cortex. [ABSTRACT FROM AUTHOR]

Objective This study sought to evaluate the toxicity and curative effect of irinotecan plus cisplatin neoadjuvant chemotherapy (NACT) for stage Ib2, IIa2, and IIb cervical cancer patients. Methods A total of 219 patients were randomly assigned to two groups: 109 patients were treated with 1–2 cycles of chemotherapy (NACT group), and 110 patients in the control group were treated directly with surgery (DS group). Patients in the NACT group were randomly assigned to two groups: 50 patients were treated with irinotecan plus cisplatin followed by surgery (IP group), and 59 patients were treated with paclitaxel plus cisplatin followed by surgery (TP group). Patients with pathological recurrence risk factors received post-operative radiotherapy. Results Survival analysis revealed no significant difference in disease-free survival (DFS) or overall survival (OS) between the NACT and DS groups. Analysis of clinicopathologic factors showed that the lymphovascular space invasion (LVSI) and deep stromal invasion rates were significantly lower in the NACT group. Grade 3/4 neutropenia and grade 3/4 diarrhea were both higher in the IP group than in the TP group. DFS and OS were similar in the IP and TP groups. Univariate analysis showed that LVSI was the only factor associated with DFS. Conclusion NACT did not improve overall survival but did reduce the number of patients who received post-operative radiotherapy. NACT consisting of irinotecan plus cisplatin for cervical cancer showed similar efficacy and higher toxicity compared with the use of paclitaxel plus cisplatin, although the toxicity was tolerable. [ABSTRACT FROM AUTHOR]

Background It is unclear whether the transcriptional subtypes of high grade serous ovarian cancer (HGSOC) apply to high grade clear cell (HGCCOC) or high grade endometrioid ovarian cancer (HGEOC). We aim to delineate transcriptional profiles of HGCCOCs and HGEOCs. Methods We used Agilent microarrays to determine gene expression profiles of 276 well annotated ovarian cancers (OCs) including 37 HGCCOCs and 66 HGEOCs. We excluded low grade OCs as these are known to be distinct molecular entities. We applied the prespecified TCGA and CLOVAR gene signatures using consensus non-negative matrix factorization (NMF). Results We confirm the presence of four TCGA transcriptional subtypes and their significant prognostic relevance (p < 0.001) across all three histological subtypes (HGSOC, HGCCOC and HGEOCs). However, we also demonstrate that 22/37 (59%) HGCCOCs and 30/67 (45%) HGEOCs form 2 additional separate clusters with distinct gene signatures. Importantly, of the HGCCOC and HGEOCs that clustered separately 62% and 65% were early stage (FIGO I/II), respectively. These finding were confirmed using the reduced CLOVAR gene set for classification where most early stage HGCCOCs and HGEOCs formed a distinct cluster of their own. When restricting the analysis to the four TCGA signatures (ssGSEA or NMF with CLOVAR genes) most early stage HGCCOCs and HGEOC were assigned to the differentiated subtype. Conclusions Using transcriptional profiling the current study suggests that HGCCOCs and HGEOCs of advanced stage group together with HGSOCs. However, HGCCOCs and HGEOCs of early disease stages may have distinct transcriptional signatures similar to those seen in their low grade counterparts. [ABSTRACT FROM AUTHOR]

• A deep learning-based phase reconstruction scheme is proposed for high-resolution multi-shot (MSH) DWI reconstruction. • Higher SNR (especially with high acceleration rates), fewer aliasing artifacts, lower ghost-to-signal-ratio (GSR), higher tracked fiber counts, and finer fiber delineation can be obtained with MSH-DWI reconstruction compared to conventional MUSE. • Single-shot (SSH) DWIs were used for training, making the proposed method readily applicable for routine clinical exams. A phase correction method for high-resolution multi-shot (MSH) diffusion weighted imaging (DWI) is proposed. The efficacy and generalization capability of the method were validated on both healthy volunteers and patients. Conventionally, inter-shot phase variations for MSH echo-planar imaging (EPI) DWI are corrected by model-based algorithms. However, many acquisition imperfections are hard to measure accurately for conventional model-based methods, making the phase estimation and artifacts suppression unreliable. We propose a deep learning multiplexed sensitivity-encoding (DL-MUSE) framework to improve the phase estimations based on convolutional neural network (CNN) reconstruction. Aliasing-free single-shot (SSH) DW images, which have been used routinely in clinical settings, were used for training before the aliasing correction of MSH-DWI images. A dual-channel U-net comprising multiple convolutional layers was used for the phase estimation of MSH-EPI. The network was trained on a dataset containing 30 healthy volunteers and tested on another dataset of 52 healthy subjects and 15 patients with lesions or tumors with different shot numbers (4, 6 and 8). To further validate the generalization capability of our network, we acquired a dataset with different numbers of shots, TEs, partial Fourier factors, resolutions, ETLs, FOVs, coil numbers, and image orientations from two sites. We also compared the reconstruction performance of our proposed method with that of the conventional MUSE and SSH-EPI qualitatively and quantitatively. Our results show that DL-MUSE is capable of correcting inter-shot phase errors with high and robust performance. Compared to conventional model-based MUSE, our method, by applying deep learning-based phase corrections, showed reduced distortion, noise level, and signal loss in high b -value DWIs. The improvements of image quality become more evident as the shot number increases from 4 to 8, especially in those central regions of the images, where g -factor artifacts are severe. Furthermore, the proposed method could provide the information about the orientation of the white matter with better consistency and achieve finer fibers delineation compared to the SSH-EPI method. Besides, the experiments on volunteers and patients from two different sites demonstrated the generalizability of our proposed method preliminarily. A deep learning-based reconstruction algorithm for MSH-EPI images, which helps improve image quality greatly, was proposed. Results from healthy volunteers and tumor patients demonstrated the feasibility and generalization performances of our method for high-resolution MSH-EPI DWI, which can be used for routine clinical applications as well as neuroimaging research. [ABSTRACT FROM AUTHOR]

Abstract: The last step in sphingolipid biosynthesis is the conversion of ceramide (Cer) to sphingomyelin (SM), which is catalyzed by sphingomyelin synthase (SMS). Two isoforms of SMS have been identified with differential subcellular localizations. It is not clear whether the two isoforms have any differences in biochemical or cellular SMS activities. This report describes a mass spectrometry (MS)-based method that was used to characterize biochemical and cellular SMS activities of the two isoforms of SMS, namely SMS1 and SMS2. Cellular extracts of SMS1 or SMS2 expressed in SF9 cells displayed significant SMS activity. When these activities were measured by MS, both SMS1 and SMS2 demonstrated similar time- and substrate-dependent SMS activity. A previously reported SMS inhibitor, D609, inhibited both SMS1 and SMS2 activity. In HEK293 cells, overexpression of either SMS1 or SMS2 significantly increased SMS activity. These studies using MS methods to measure SMS activity of SMS1 and SMS2 represent the first quantitative measurement of SMS activities. The establishment of quantitative biochemical and cellular SMS assays may help to facilitate the discovery of novel SMS1- or SMS2-specific inhibitors. [Copyright &y& Elsevier]

Abstract: Purpose: Environmental exposure to arsenic is an important public health issue. The effects of arsenic on different tissues and organs have been intensively studied. However, the effects of arsenic on bone marrow mesenchymal stem cells (MSCs) have not been reported. This study is designed to investigate the cell death process caused by arsenite and its related underlying mechanisms on MSCs. The rationale is that absorbed arsenic in the blood circulation can reach to the bone marrow and may affect the cell survival of MSCs. Methods: MSCs of passage 1 were purchased from Tulane University, grown till 70% confluency level and plated according to the experimental requirements followed by treatment with arsenite at various concentrations and time points. Arsenite (iAsIII) induced cytotoxic effects were confirmed by cell viability and cell cycle analysis. For the presence of canonic apoptosis markers; DNA damage, exposure of intramembrane phosphotidylserine, protein and m-RNA expression levels were analyzed. Results: iAsIII induced growth inhibition, G2-M arrest and apoptotic cell death in MSCs, the apoptosis induced by iAsIII in the cultured MSCs was, via altering Bcl-2 family proteins and by involving intrinsic pathway. Conclusion: iAsIII can induce apoptosis in bone marrow-derived MSCs via Bcl-2 family proteins, regulating intrinsic apoptotic pathway. Due to the multipotency of MSC, acting as progenitor cells for a variety of connective tissues including bone, adipose, cartilage and muscle, these effects of arsenic may be important in assessing the health risk of the arsenic compounds and understanding the mechanisms of arsenic-induced harmful effects. [Copyright &y& Elsevier]

Abstract: The free fatty acid receptor, GPR40, is implicated in the pathophysiology of type 2 diabetes, and is a new potential drug target for the treatment of type 2 diabetes. Its antagonist is thought to be not only a useful chemical probe for further exploring the function of GPR40 but also a lead structure for drug development. With virtual screening based on a homology model followed by a cell-based calcium mobilization assay, we found that sulfonamides are a new class of small organic antagonists for GPR40. One of the compounds, DC260126, dose-dependently inhibited GPR40-mediated Ca2+ elevations stimulated by linoleic acid, oleic acid, palmitoleic acid and lauric acid (IC50: 6.28±1.14, 5.96±1.12, 7.07±1.42, 4.58±1.14μM, respectively), reduced GTP-loading and ERK1/2 phosphorylation stimulated by linoleic acid in GPR40-CHO cells, suppressed palmitic acid potentiated glucose-stimulated insulin secretion, and negatively regulated GPR40 mRNA expression induced by oleic acid in Min6 cells. [Copyright &y& Elsevier]

Abstract: Objective: Tight junction (TJ) proteins claudin-3 and claudin-4 may be differentially expressed in uterine serous papillary carcinoma (USPC), a rare form of endometrial cancer characterized by a particularly poor prognosis. Our aim was to determine the expression pattern and prognostic relevance of claudin-3 and claudin-4 in a large cohort of endometrial cancer patients of diverse histological type and stage. Methods: Claudin-3 and claudin-4 expression was studied in a cohort of 287 patients with endometrial cancer including 137 cases of USPC or clear-cell histology using immunohistochemistry. Patients were completely surgically staged. Outcome data is available on all 287 patients. Results: The rate of claudin-3 and claudin-4 expression was significantly higher in USPC and clear-cell endometrial cancer compared to endometrioid endometrial cancer (claudin-3: 78% and 61% versus 38%, p <.0001; claudin-4: 56% and 44% versus 9%, p <.0001). Furthermore, expression of both TJ proteins was significantly associated with poor clinical outcome (claudin-3, DFS RR 1.70, p =.0087, OS RR 1.62, p =.0247; claudin-4, DFS RR 2.66, p <0.0001, and OS RR 2.50, p <0.0001). However, both markers did not maintain prognostic independence in multivariate analyses, as their expression was tightly associated with more advanced disease stages (p <.0001 for both), and higher nuclear grade (p <.0001 for both). Conclusion: These clinical observations confirm the hypothesis based on preclinical evidence that increased expression of claudin-3 and claudin-4 may contribute to the aggressive phenotype of endometrial cancer of serous papillary or clear-cell histology and suggest their potential utility as diagnostic biomarkers and possible targets for therapeutic intervention. [Copyright &y& Elsevier]

Abstract: ADAMTS-4 (aggrecanase-1) is a metalloprotease that plays a role in aggrecan degradation in the cartilage extracellular matrix. In order to understand the regulation of ADAMTS-4 gene expression we have cloned and characterized a functional 4.5kb human ADAMTS-4 promoter. Sequence analysis of the promoter revealed the presence of putative binding sites for nuclear factor of activated T cells (NFAT) and Runx family of transcription factors that are known to regulate chondrocyte maturation and differentiation. Using promoter–reporter assays and mRNA analysis we have analyzed the role of chondrocyte-expressed transcription factors NFATp and Runx2 and have shown that ADAMTS-4 is a potential downstream target of these two factors. Our results suggest that inhibition of the expression/function of NFATp and/or Runx2 may enable us to modulate aggrecan degradation in normal physiology and/or in degenerative joint diseases. The ADAMTS-4 promoter would serve as a valuable mechanistic tool to better understand the regulation of ADAMTS-4 expression by signaling pathways that modulate cartilage matrix breakdown. [Copyright &y& Elsevier]

Abstract: A G-protein coupled receptor to niacin (nicotinic acid) was identified recently but the physiological/pharmacological role of the receptor remains poorly defined. We present our studies to demonstrate that HM74A, but not HM74, binds niacin at high affinities and effectively mediates Gi signaling events in human embryonic kidney HEK293 cells as well as in 3T3L1 adipocytes expressing HM74A. Furthermore, HM74A, but not HM74, expressed in differentiated 3T3L1 adipocytes effectively mediated inhibition of lipolysis by niacin. Our results provided direct evidence indicating that HM74A, but not HM74, was sufficient to mediate anti-lipolytic effect of niacin in adipose tissue. [Copyright &y& Elsevier]

Accumulating evidence suggests that vitamin D (VD) has a therapeutic effect on non-alcoholic fatty liver disease (NAFLD). Pyroptosis and gut microbiota have been recognized as critical factors of the progression of NAFLD. However, the effect of VD on the pyroptosis and gut microbiota in NAFLD remains inconclusive. Herein, rats were fed high fat diet (HFD) for 12 weeks and concurrently treated with 5 μ g/kg 1,25(OH) 2 D 3 twice a week. BRL-3A cells were stimulated with 0.4 mmol/L palmitic acid (PA) and 1 μ g/ml lipopolysaccharide (LPS) for 16 h and treated with 10−6 mol/L 1,25(OH) 2 D 3. Effect of VD on the hepatic injury, lipid accumulation, activation of NLRP3 inflammasome and pyroptosis was determined in vivo and in vitro. Next, gasdermin D N -terminal (GSDMD-N) fragment was overexpressed in BRL-3A cells to investigate the role of pyroptosis in the therapeutic effect of VD on NAFLD. In addition, gut microbiota in NAFLD rats was also analyzed. Results showed that VD attenuated HFD-induced hepatic injury in vivo and PA-LPS-induced impairment of cell viability in vitro , and inhibited lipid accumulation, activation of NLRP3 inflammasome and pyroptosis in vivo and in vitro. GSDMD-N fragment overexpression suppressed the protective effect of VD on PA-LPS-induced activation of NLRP3 inflammasome, impairment of cell viability and lipid accumulation, indicating that VD might attenuate NAFLD through inhibiting pyroptosis. Additionally, VD also restored HFD-induced gut microbiota dysbiosis by increasing the relative abundance of Lactobacillus and reducing that of Acetatifactor , Oscillibacter and Flavonifractor. This study provides a novel mechanism underlying VD therapy against NAFLD. • Vitamin D inhibited activation of NLRP3 inflammasome and pyroptosis in NAFLD rat. • Vitamin D might attenuate HFD-induced NAFLD by inhibiting pyroptosis in NAFLD rat. • Vitamin D restored HFD-induced gut microbiota dysbiosis in NAFLD rat. [ABSTRACT FROM AUTHOR]